Mesothelin is shed from cells by the action of membrane bound proteases. We believe shedding is important for the carcinogenic effect of mesothelin. We have previously established that ADAM 17 is important for mesothelin shedding in KLM-1 cells and evaluated the effect of shedding inhibitors. These only have modest activity. We have recently found that the enzymes responsible for shedding vary among cell line. In some cell lines ADAM17 is important. In others BACE2 is important. In others, the enzyme responsible for shedding is not clear. We have initiated a collaboration with GaloreTex to identify new mesothelin specific inhibitors which could be useful in cancer treatment. Initial experiments have identified peptides that inhibit shedding by KB cells.